27- Immunodeficiency

• Primary Immunodeficiencies

  Inherited genetic defects
• SCID


  Severe combined immunodeficiency, defect in T cells or T cell function
• T cells (cytokines) needed for complete B cell activation, so SCID is severe
• Genetic defect in SCID

  Removes T cells from periphery
• 5 categories of immunodeficiency defects

  • Failure in development of daughter cells: prevents myeloid and lymphoid development
  • Premature death of lymphocytes: DNA metabolism defect
  • Rag 1/2 expression impaired: defective V(D)J rearrangement, no pre TCR or pre BCR
  • Defective cytokine signaling: IL-2 and IL-7 needed for T cell proliferation, IL-15 and IL-35 cells needed to stay alive
  • Disruptions in TCR/BCR signaling molecules: cells will apoptose if can't get past this stage
• Partial immunodeficiency


  Hyper IgM syndrome, no CD40 ligand so no isotype switching or memory cells
• B cell immunodeficiency


  1. linked agammaglobulinemia, low IgG and no other classes, defect in BTK, lack of signaling cells arrested at Pro-B to Pre-B cell stage
• Replacement therapy for immunodeficiency is usually difficult, can be easier if it's something soluble like cytokines
• If possible, can try to replace protein, cell type, or defective gene for immunodeficiency
• Primary Immunodeficiency


  Genetic defects
• Secondary Immunodeficiency


  Caused by exposure to external agents, mostly affects the adaptive immune system
• If innate system defects, secondary immunodeficiency is usually fatal
• Inheritance patterns of immunodeficiencies

  • Autosomal recessive is most common
  • Autosomal dominant: person is likely to die before they can reproduce
  • X-linked: can be carried by female and not express it, but if a male gets it it can be bad
• Secondary Immunodeficiency


  Can be induced by drugs, pathogens, age, environment
• AIDS


  Caused by Human Immunodeficiency Virus, main symptom is decrease in CD4 cells but also affects macrophages
• HIV infection

  1. Relies on chemokine receptors as co-receptors

  2. Binds to CD4 on macrophages with co-receptor CCR5 and gets inside, delivers virus to T cells in lymph node

  3. Can then bind to CXCR, infect T cells, and through life cycle T cells get taken out

  4. Replicates only in CD4 cells

  5. Lives in T cell quiescently: every time T cell activates, it reactivates, goes through life cycle, takes out T cells and moves onto new T cells

  6. Uses NFAT and NFKB
• What kills AIDS patients: usually secondary infections due to the lack of T cells making the person severely immunodeficient
• Treatment for HIV/AIDS

  • Chemokine receptor antagonist
  • Inhibit fusion
  • Inhibit reverse transcription
  • Inhibit integrase
  • Inhibit protease
• Scid Causes People to Die From?

  Infectins normal people can handle